Macrophage migration inhibitory factor (MIF) is a cytokine that plays a central role in numerous inflammatory diseases (Morand et al., Nature Rev. Drug. Disc. 2006, 5, 399-410; Greven et al., Expert Opin. Ther. Targets, 2010, 14, 253-264; Asare et al., Thromb. Haemost. 2013, 109, 391-398). MIF is widely expressed in both immune and non-immune cells including macrophages, endothelial cells, and T-cells. Upon activation the cells release MIF, which promotes the release of other inflammatory cytokines such as TNF-α and IL-1. Excessive or chronic inflammatory response is associated with tissue damage and autoimmune diseases such as rheumatoid arthritis, Crohn's disease, and lupus erythematosus. The connection between inflammatory disease and cancer is also well-established, and MIF has been shown to enhance cell proliferation by inhibiting accumulation of the tumor suppressor p53 and by promotion of angiogenesis (Conroy et al., Q. J. Med. 2010, 103, 831-836). MIF is over-expressed in many cancer cells and can serve as a marker for disease progression. Furthermore, MIF in cancer cells is protected from degradation by Hsp90, which has led to proposed targeting of Hsp90 as an indirect way of inhibiting MIF function (Schulz et al., Curr. Opin. Oncol., 2014, 26, 108-113). Disruption of the inflammatory cascade and restoration of normal p53 levels have clear implications for the potential therapeutic value of inhibitors of MIF signaling. Indeed, immunoneutralization of MIF or deletion of the MIF gene is known to suppress inflammatory response, tumor growth, and angiogenesis. At the molecular level, what is needed is interference with the interaction between MIF and its cell-surface receptor CD74.
MIF is a toroid-shaped, trimeric protein with a total of 342 amino acid residues. Besides its role as a cytokine, MIF is a keto-enol tautomerase. Though the enzymatic activity appears to be vestigial in humans, there are three tautomerase active sites at the interfaces of the monomer units opening to the outside of the toroid. The presence of the tautomerase sites presents an opportunity for complexation of a tautomerase inhibitor that may also interfere with MIF/CD74 binding. This notion has been supported by many studies that show correlation between the inhibition of the enzymatic and biological activities of MIF (Senter et al., Proc. Natl. Acad. Sci. U.S.A., 2002, 99, 144-149). For example, this has been demonstrated through assay results for tautomerase activity, MIF/CD74 binding, and MIF-induced phosphorylation of ERK1/2 in inflamed cells, production of interleukins, glucocorticoid overriding ability, and macrophage chemotactic migration (Senter et al; Cournia et al., J. Med. Chem. 2009, 52, 416-424; Hare et al., Bioorg. Med. Chem. Lett. 2010, 20, 5811-5814; Jorgensen et al., Bioorg. Med. Chem. Lett. 2010, 20, 7033-7036; Orita et al., Curr. Pharm. Des. 2002, 8, 1297-1317; Garai et al., Curr. Med. Chem. 2009, 16, 1091-1114; Xu et al., Drug Disc. Today 2013, 18, 592-600; Xu et al., J. Med. Chem. 2014, 57, 3737-3745; Tsai et al., J. Biomol. Screen. 2014, 19, 1116-1123).